We propose to test the hypothesis that inhibitors of COX-2 and 5-LOX and certain retinoids or their combinations can be effective chemopreventive agents against lung cancer by inducing apoptosis. The objectives of this project are: to identify potentially effective agents for lung cancer prevention among inhibitors of COX-2, 5-LOX, and retinoids or a combination of these agents using in vitro and in vivo systems and to provide insight into their mechanism of action on normal, premalignant, and malignant lung epithelial cells. These objectives will be accomplished by the following specific aims: Specific Aim 1: To determine the expression of COX-2 and 5-LOX in bronchial biopsies collected during the chemoprevention trial at baseline and after treatment with celecoxib or placebo and to correlate the results with the expression of the proliferation marker Ki67. Specific Aim 2: To determine the efficacy of COX-2 inhibitors (celecoxib: and NS398) and 5-LOX inhibitors (MK866; REV5901, ABT-761) used as single agents and in combination with each other and with certain retinoids (all-trans-retinoic acid, 4HPR, and CD437) in suppression of cell growth and induction of apoptosis of normal, immortalized, premalignant, transformed and tumorigenic lung cells in vitro and to relate these effects to the expression and activity of COX-2, 5-LOX, and retinoid receptors. Specific Aim 3: To determine the mechanisms underlying the activities of the most effective agents and their combinations. Emphasis will be given to analysis of biochemical and molecular changes in cell cycle and apoptosis related genes (cyclins, BCl2 family members, death receptors, mitochondrial reactive oxygen species generation and inner membrane potential, cytochrome C, caspases and their substrates). Specific Aim 4: To determine the efficacy of selected COX-2 inhibitors and 5-LOX inhibitors used as single agents and in combination with each other and with selected retinoids on the incidence of lung adenomas and adenocarcinomas that develop spontaneously or after exposure to the tobacco carcinogen NNK in transgenic mice, which express antisense retinoic acid receptor beta and in A/J mice exposed to NNK. The mechanisms underlying chemopreventive effects of above agents will be explored. Significance: This study will assess systematically the mechanisms of action of COX-2- and 5-LOX inhibitors and their combinations with retinoids to suppress growth and induce apoptosis of normal, premalignant and malignant lung epithelial cells in vitro and lung carcinogenesis in vivo in animal models and to assess their potential for use in future chemoprevention trials.